Chromatin structure organization is crucial for regulating many fundamental cellular processes. Perturbations of chromatin structure have been linked to many human genetic diseases including cancer. However the molecular mechanism that regulates the assembly of higher-order chromatin structure remains poorly understood. Our previous work identified the cellular protein Brd4 (bromodomain-containing protein 4) as a novel chromatin receptor for cervical cancer-associated papillomaviruses. Brd4 plays an important role in cell cycle regulation and cancer. Our functional studies have established the Brd4 function in chromatin structure maintenance. Brd4 is also a target of the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), and the genetic translocation t(15;19) that defines a highly lethal carcinoma. We hypothesize that abrogation of the Brd4 cellular function in chromatin structure maintenance underlies the oncogenic mechanisms for the tumorigenic viruses- and translocation-associated carcinoma. Our proposed studies will apply recently developed Stochastic Optical Reconstruction Microscopy (STORM) technology and in situ single cell imaging to further examine Brd4 function in chromatin structure organization. We will investigate the mechanisms by which Brd4 mediates the chromatin structure maintenance. Using the cancer-associated viral proteins and genetic mutations as molecular probes, we will further explore the mechanisms by which these oncogenic agents abrogate the Brd4 function to contribute to malignant progression. These integrated studies will provide greater understanding of the Brd4 function in higher-order chromatin organization and cancer. This study will present a paradigm for investigating the molecular mechanisms of other bromodomain- containing chromatin adaptors. The outcome of this study will offer promising leads for developing efficient anti-cancer therapeutic strategies.

Public Health Relevance

We have previously identified the bromodomain protein Brd4 as a host receptor for human papillomaviruses that are strongly associated with cervical cancer. In this grant, we propose to investigate the molecular mechanisms underlying the Brd4 function in chromatin structure maintenance. We will determine how abrogation of Brd4 cellular function by tumor viruses and genetic mutation could cause human cancers. This study will provide new insights for developing efficient anti-cancer therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148768-04
Application #
8434755
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Okano, Paul
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$302,718
Indirect Cost
$113,519
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tsang, Sabrina H; Wang, Xin; Li, Jing et al. (2014) Host DNA damage response factors localize to merkel cell polyomavirus DNA replication sites to support efficient viral DNA replication. J Virol 88:3285-97
Wang, Ranran; Liu, Wei; Helfer, Christine M et al. (2014) Activation of SOX2 expression by BRD4-NUT oncogenic fusion drives neoplastic transformation in NUT midline carcinoma. Cancer Res 74:3332-43
Li, Jing; Li, Qing; Diaz, Jason et al. (2014) Brd4-mediated nuclear retention of the papillomavirus E2 protein contributes to its stabilization in host cells. Viruses 6:319-35
Helfer, Christine M; Yan, Junpeng; You, Jianxin (2014) The cellular bromodomain protein Brd4 has multiple functions in E2-mediated papillomavirus transcription activation. Viruses 6:3228-49
Liu, W; Stein, P; Cheng, X et al. (2014) BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos. Cell Death Differ 21:1950-60
Wang, Xin; Helfer, Christine M; Pancholi, Neha et al. (2013) Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. J Virol 87:3871-84
Li, Jing; Wang, Xin; Diaz, Jason et al. (2013) Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation. J Virol 87:9173-88
Helfer, Christine M; Wang, Ranran; You, Jianxin (2013) Analysis of the papillomavirus E2 and bromodomain protein Brd4 interaction using bimolecular fluorescence complementation. PLoS One 8:e77994
Wang, Ranran; Li, Qing; Helfer, Christine M et al. (2012) Bromodomain protein Brd4 associated with acetylated chromatin is important for maintenance of higher-order chromatin structure. J Biol Chem 287:10738-52
Yan, Junpeng; Diaz, Jason; Jiao, Jing et al. (2011) Perturbation of BRD4 protein function by BRD4-NUT protein abrogates cellular differentiation in NUT midline carcinoma. J Biol Chem 286:27663-75

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